Melasma: Management

INTRODUCTION — The management of melasma is often challenging, with incomplete responses in many cases and frequent relapses [1,2]. A combination of therapies targeting multiple pathogenic elements, such as photodamage, inflammation, aberrant vascularity, and abnormal pigmentation, generally provides the best clinical outcomes [3]. The available therapeutic armamentarium includes a variety of agents that inhibit the biosynthesis of melanin and increase epidermal turnover and chemical peels and lasers that accelerate the removal of melanin, without influencing melanin synthesis or melanosome transfer from melanocytes to keratinocytes [4-6].

This topic presents an overview of treatments for melasma that can be used as part of a comprehensive management plan that should be individualized to each patient [1-3,7-10]. The pathogenesis, clinical manifestation, and diagnosis of melasma are discussed separately. Other congenital and acquired hyperpigmentation disorders are also discussed separately.

●(See "Melasma: Epidemiology, pathogenesis, clinical presentation, and diagnosis".)

●(See "Congenital and inherited hyperpigmentation disorders".)

●(See "Acquired hyperpigmentation disorders".)

●(See "Postinflammatory hyperpigmentation".)

PRETREATMENT EVALUATION — Pretreatment evaluation of the patient includes assessment of severity and duration of melasma, specific risk and trigger factors, level of adherence to treatment, and willingness to adopt strict photoprotection measures. Moreover, use and response to previous treatments should also be assessed. As melasma is often influenced or triggered by hormone therapies, clinicians should personalize recommendations regarding the use of hormones, based on the unique needs of each patient [7]. (See "Melasma: Epidemiology, pathogenesis, clinical presentation, and diagnosis", section on 'Risk and trigger factors'.)

PATIENT EDUCATION — Patient education has a key role in the management of melasma. Clinicians should educate patients about the risk factors and triggers for melasma; the importance of daily use of a broadband sunscreen that protects against ultraviolet (UV), visible, and even infrared light; and the importance of consistent use of maintenance therapy to minimize the risk of recurrence [3,8,11]. (See 'Photoprotection' below.)

APPROACH TO TREATMENT — There is no standard therapy for melasma. Although several treatment guidelines and algorithms have been proposed, they are, in most cases, based on expert consensus rather than on evidence from robust, large, randomized studies [7,9,12,13]. In most cases, a multimodality approach is required, incorporating photoprotection, skin lighteners, exfoliants, antioxidants, and resurfacing procedures, based on the patient's characteristics and clinical presentation [14]. Our approach to the management of melasma is illustrated in the algorithm (algorithm 1).

Photoprotection — Strict photoprotection, including sun avoidance, sun-protective clothing, and broad-spectrum sunscreens, is an essential component of all treatment and prevention regimens for melasma [2,3,7,10,11].

Broad-spectrum sunscreens — We suggest daily use of a broad-spectrum sunscreen with a sun protection factor (SPF) of 50 or higher. Sunscreen should be applied in an adequate amount in the morning and reapplied every two to three hours while outdoors. (See "Selection of sunscreen and sun-protective measures".)

In a Moroccan study, 185 pregnant women in their first trimester (15 percent with a previous history of melasma and 6 percent with current melasma) were asked to apply the sunscreen every two hours [15]. Skin color stayed the same or became lighter in 79 percent of the women throughout their pregnancy, and only five women (2.7 percent) developed new-onset melasma. The authors previously reported that 53 percent of pregnant women in the same geographical area developed melasma during pregnancy. Eight of the 12 women with pre-existing melasma improved.

Tinted (colored) sunscreens — Several studies documented the role of visible light in inducing pigmentation in persons with darker skin types [16,17]. Chemical and mineral (zinc oxide- and titanium dioxide-based) broad-spectrum sunscreens do not provide optimal protection from visible light. The most efficacious visible light sunscreens contain iron oxide in concentrations above 3%. Of note, iron oxide is the major pigment used in tinted sunscreens and colored topical products and cosmetics [18,19]. (See "Selection of sunscreen and sun-protective measures".)

Several studies support the use of ultraviolet (UV) and visible light protection in the treatment and prevention of melasma.

●An eight-week, randomized trial assessed the efficacy of a broad-spectrum sunscreen with an SPF ≥50 with or without iron oxide as a visible light-absorbing pigment in 68 patients with melasma receiving 4% hydroquinone as a depigmenting treatment [20]. A greater improvement in the Melasma Area and Severity Index (MASI) score and colorimetry occurred in the group using the combination visible light and broad-spectrum sunscreen formulation compared with the group using the broad-spectrum sunscreen only.

●Another randomized study performed in the spring and summer compared two identical sunscreen formulations, with the exception that one was tinted and contained iron oxide (UV plus visible light protection) and the other did not (UV light protection only) [11]. Thirty-nine patients applied the cream twice daily, with an additional application every 2 hours and 30 minutes before exposure to sunlight. Maximal reduction in the MASI score occurred in the group using the UV and visible light formulation.

First-line therapies — Topical skin-lightening agents are the first-line therapy for melasma (algorithm 1). (See 'Topical skin-lightening agents' below.)

●Mild melasma – For patients with mild melasma, we suggest hydroquinone 4% cream as first-line therapy. Hydroquinone can be applied to the affected areas once or twice daily for two to four months and up to six months, followed by maintenance treatment for six months or longer. (See 'Hydroquinone' below and 'Maintenance therapy and prevention of relapse' below.)

There is considerable variation among clinicians in their prescribing practices for hydroquinone, regarding both the concentration used and the treatment duration. In the authors' experience, hydroquinone can be safely and effectively used beyond six months, if needed. In many cases, however, a rotational treatment that cycles on and off hydroquinone and non-hydroquinone skin-lightening agents seems to optimize outcomes. (See 'Non-hydroquinone agents' below.)

Non-hydroquinone skin lighteners, such as azelaic acid, kojic acid, or niacinamide, alone or in combinations, can be used as alternative first-line therapies, particularly in patients who do not tolerate or have a demonstrated allergy to hydroquinone. Of note, azelaic acid is one of a few agents that, if needed, can be used in pregnant women. (See 'Azelaic acid' below.)

●Moderate to severe melasma – For patients with moderate to severe melasma, the fluocinolone, hydroquinone, and tretinoin triple combination cream (TCC) is preferred to hydroquinone 4% cream as initial treatment (picture 1). The cream is applied nightly for two to four months. The TCC is the only US Food and Drug Administration-approved melasma treatment. (See 'Triple combination cream' below.)

Second-line therapies — Chemical peels and oral tranexamic acid are second-line therapies for patients with melasma that does not respond to topical therapies alone (algorithm 1). (See 'Chemical peels' below and 'Oral agents' below.)

●Superficial chemical peels – Superficial chemical peels commonly used for the treatment of melasma include glycolic acid, other alpha-hydroxy acids, salicylic acid, Jessner's peel, and trichloroacetic acid (table 1). Trichloroacetic acid is not marketed in the United States and Canada. Several sessions (approximately five to six) administered at two- to four-week intervals can be used as an adjunct to regular use of hydroquinone or non-hydroquinone lightening agents (table 2). Because chemical peels temporarily remove epidermal melanin without affecting melanogenesis or melanocytes, patients should be aware that any improvements will probably be temporary. (See 'Chemical peels' below and "Chemical peels: Procedures and complications".)

Skin priming is essential to optimize outcomes with chemical peels. Priming, or preparing the skin, involves the application of topical skin-lightening agents, such as hydroquinone and tretinoin, prior to the peeling procedure, with the aim of enhancing the effect of the chemical peel and decreasing the risk of postinflammatory hyperpigmentation [21]. Priming should be done for at least two to four weeks. Lightening agents can be continued up to the time of peeling, whereas tretinoin should be discontinued at least 7 to 10 days before the procedure. Tretinoin significantly increases the depth of dermal penetration of the peeling agent, which can lead to untoward complications. (See "Chemical peels: Procedures and complications", section on 'Skin preparation'.)

●Oral tranexamic acid – Oral tranexamic acid, a hemostatic agent with antiplasmin activity, has shown efficacy in the treatment of melasma at an average dose of 250 mg twice daily [22-24]. However, relapses invariably occur upon discontinuing oral therapy. In the United States, 650 mg tablets are available. Patients are instructed to take one tablet daily or one-half of a tablet twice daily.

Although the dose used in clinical studies for the treatment of melasma is considerably lower than that used to treat hemorrhagic conditions (3500 mg daily), general concerns linger regarding the safety profile, given tranexamic acid's propensity to induce thromboembolic phenomena [10]. Therefore, patients should be thoroughly screened for thrombotic risk factors before starting oral tranexamic acid (table 3) [3,25]. (See "Overview of the causes of venous thrombosis".)

Third-line therapies — Lasers and light therapies are third-line therapies for melasma, appropriate for patients in whom topical treatments and often chemical peels have failed to produce adequate improvement (algorithm 1) [6]. Importantly, lasers and light sources should be used with great care and caution in individuals with darkly pigmented skin due to the risk of postinflammatory hyperpigmentation. (See 'Lasers and light therapies' below.)

Patients should be informed that lasers and light therapies are not cures for melasma. Indeed, approximately one-half of patients experience a recurrence within three to six months of the end of treatment, irrespective of the device used. Moreover, the recurrence may be associated with more intense pigmentation, which may be recalcitrant to subsequent treatment. Thus, clinicians should counsel patients about the importance of adhering to a maintenance regimen to minimize the risk of recurrence following laser or light therapy [6]. (See 'Maintenance therapy and prevention of relapse' below.)

Maintenance therapy and prevention of relapse — Routine approaches for prevention of relapse involve the aggressive use of broad-spectrum and visible light sunscreens as well as maintenance treatment with non-hydroquinone lighteners, such as azelaic acid, kojic acid, niacinamide, and retinoids, all of which are commonly used in the authors' practice (table 2 and algorithm 1). Additionally, intermittent use of hydroquinone 4% cream or TCC twice weekly can be incorporated in the maintenance regimen to maintain clearance.

Despite this approach with the available armamentarium of agents, however, relapses are common. Relapses require resuming active treatment.

Cosmetic camouflage — Cosmetic camouflage is a technique that uses makeup to conceal skin lesions and normalize the appearance of the skin [26]. It can mitigate the psychosocial impact of melasma and improve the patient's quality of life [3,27,28]. Anhydrous (waterproof) foundations that contain titanium dioxide, zinc oxide, and iron oxide provide a dual benefit, as they act as cosmetic concealers and sunscreen. Cosmetic camouflage can be used during active treatment.

TOPICAL SKIN-LIGHTENING AGENTS — A large number of topical skin-lightening agents have been used for the treatment of melasma. Many of them act as tyrosinase inhibitors or interfere with other steps in melanin production and transfer (table 2). Novel agents that are also used as primary or maintenance agents include combination hydroquinone-free preparations and cysteamine [10]. (See 'Non-hydroquinone agents' below.)

Hydroquinone — Topical hydroquinone was first noted to lighten the skin in 1936 and was initially used to treat clinical hyperpigmentation in 1961 [2]. It inhibits the conversion of tyrosine to melanin by competitively inhibiting tyrosinase [29-31]. Inhibition of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis by melanocytes and increased melanosome degradation may also contribute to hydroquinone's mechanism of action [3,5,32].

Numerous hydroquinone formulations are now available, either as monotherapy or combined with other skin-lightening agents or exfoliants, such as glycolic acid or tretinoin [2,33] (see 'Triple combination cream' below). Concentrations range from 2% or less, in over-the-counter (OTC) formulations, to 4% or more, available by prescription only [2]. Hydroquinone rapidly oxides, and tretinoin may reduce hydroquinone oxidation [9,33].

Efficacy — A 2009 systematic review of 31 randomized and uncontrolled studies assessing topical treatments, chemical peels, lasers, and other therapies in Latin American patients with melasma concluded that hydroquinone 4% monotherapy, triple combination cream (TCC; hydroquinone 4%, tretinoin 0.05%, and fluocinolone acetate 0.01%), and double combinations (eg, 4% hydroquinone and 0.1% tretinoin) were the most appropriate treatments for mild melasma, while TCC was the most appropriate first-line treatment for moderate to severe melasma [7].

A 2010 systematic review of 20 randomized trials (2125 participants) examining the efficacy of 23 treatments concluded that TCC was more effective at lightening melasma compared with hydroquinone 4% alone or dual combinations of hydroquinone and tretinoin or hydroquinone and fluocinolone acetonide [34]. However, the included studies were generally of poor quality and could not be pooled for analysis due to considerable heterogeneity.

Another meta-analysis of 36 randomized trials evaluating the efficacy of self-applied topical interventions for melasma confirmed that TCC is more effective at lightening melasma than its individual components hydroquinone and tretinoin [35].

Adverse effects — Hydroquinone can lighten normal skin pigmentation. However, pigment will return to normal upon discontinuation of the product [36]. Acute complications following hydroquinone application include irritation (the most common reaction), allergic contact dermatitis, postinflammatory hyperpigmentation, and hypopigmentation [2]. Patients may develop erythema and peeling after using TCC [4]. The irritation (eg, itching, burning, and stinging sensations) was generally mild [2].

Other chronic adverse events associated with hydroquinone include nail discoloration, ocular side effects, and exogenous ochronosis. Nail discoloration seems to be a result of oxidation and polymerization of byproducts due to chronic hydroquinone use. Ocular complications are rare [30]. Exogenous ochronosis typically presents as asymptomatic hyperpigmentation, erythema, papules, papulonodules, and gray-blue colloid milia on sun-exposed skin and often proves difficult to treat (picture 2 and picture 3 and picture 4) [7,30]. (See "Topical skin-lightening agents: Complications of use in the nonmedical setting", section on 'Hydroquinone'.)

Despite extensive use in the United States, hydroquinone-related exogenous ochronosis is uncommon, especially compared with the number of cases in Africa [37]. The routine use of sunscreens and the relative absence of resorcinol-containing and hydroethanolic formulations (which may increase hydroquinone absorption) in developed countries may account for these geographical differences [30]. Nevertheless, hydroquinone is banned in some African and European countries [10].

There have been concerns about a possible link between hydroquinone and malignancies. However, hydroquinone occurs naturally in some foods, including coffee, tea, wheat, pears, and blueberries. No retrospective case series, prospective study, or epidemiologic evaluation in the United States suggests a causative link between hydroquinone and malignancies [33]. Another literature review revealed no cases of skin cancer, internal malignancies, or hepatic dysfunction related to topical hydroquinone use for skin lightening [10]. In general, hydroquinone and TCC are well tolerated and supported by a long history of use.

Contraindications — Hydroquinone is contraindicated in pregnant and breastfeeding women and in patients with documented allergy.

Triple combination cream — The fluocinolone, hydroquinone, and tretinoin cream, also called triple combination cream (TCC), is the only US Food and Drug Administration-approved melasma treatment [38]. The various components of the TCC have complementary effects that act synergistically to produce the clinical benefits.

●Hydroquinone is a competitive tyrosinase inhibitor that inhibits the conversion of tyrosine to melanin. (See 'Hydroquinone' above.)

●Topical retinoids (including tretinoin, adapalene, and tazarotene) improve melasma by promoting turnover of keratinocytes [3]. Topical retinoids may also inhibit tyrosinase as well by enhancing the penetration of hydroquinone [2,33]. However, the onset of action when retinoids are used as monotherapy is usually longer than hydroquinone, taking approximately 24 weeks for significant lightening to emerge [39]. Tretinoin is available in various doses (from 0.01 to 0.1%) and formulations (eg, creams, gels, lotions, and solutions) but is not approved in the United States as monotherapy for melasma [2].

●Topical corticosteroids may directly inhibit melanogenesis by reducing production of inflammatory mediators, such as prostaglandins and leukotrienes [2]. Few studies, however, have assessed the efficacy of corticosteroids as monotherapy [2]. The topical corticosteroid in the TCC also reduces irritation induced by the other two ingredients [9].

Efficacy — The efficacy of the TCC for the treatment of melasma has been evaluated in randomized trials and in a systematic review [34,40,41].

●In a randomized trial, 260 East Asian and Southeast Asian patients with moderate to severe melasma were treated with the TCC or hydroquinone 4% cream [40]. At eight weeks in the per protocol analysis, more participants in the TCC group than in the hydroquinone group had a global severity score of "none" or "mild" (64 versus 39 percent). Similar results were obtained in the intention-to-treat population (59 versus 36 percent). Adverse events were reported in 49 percent of patients in the TCC group and 14 percent of those in the hydroquinone group and included erythema, irritation, desquamation, and skin discomfort.

●In another study, 641 patients received the TCC or dual combination creams (tretinoin 0.05% and hydroquinone 4%, tretinoin 0.05% and fluocinolone acetonide 0.01%, hydroquinone 4% and fluocinolone acetonide 0.01%) twice daily for eight weeks [41]. In the TCC group, 26 percent had complete clearing of melasma compared with 9.5, 1.9, and 2.5 percent in each of the dual combination creams, respectively. Adverse effects included erythema, desquamation, burning, dryness, and pruritus.

●A 2010 systematic review of 20 randomized trials (2125 participants) examining the efficacy of 23 treatments concluded that the TCC was more effective at lightening melasma compared with hydroquinone 4% alone or dual combinations of hydroquinone and tretinoin or hydroquinone and fluocinolone acetonide [34]. The included studies were heterogeneous and generally of low quality.

Intermittent use of the TCC may be effective in preventing melasma relapse in some patients [42,43].

●In a randomized trial, 242 patients with moderate to severe melasma who had no or mild melasma after eight weeks of daily TCC treatment were assigned to a six-month maintenance treatment with the TCC in a twice-weekly or tapering regimen (three times weekly for one month, two times weekly for two months, and one time weekly for one month) [42]. At six months, 54 and 53 percent of patients were relapse-free in the two groups, respectively.

●In an open-label study by the author's group, 52 patients applied the TCC daily for 12 weeks. Of these, 27 patients who were clear or almost clear at 12 weeks started maintenance therapy with the TCC twice weekly for an additional 12 weeks, while 25 patients who were not clear or almost clear at 12 weeks continued daily treatment [43]. Of the 27 patients on maintenance therapy, 21 relapsed and restarted daily treatment, and 6 remained on maintenance TCC throughout follow-up. At 24 weeks, 68 percent of patients in all groups combined were clear or had mild melasma. Scores on a 10-point patient satisfaction score (where 10 was the best) averaged approximately 9, and patients wanted to continue treatment [43].

Contraindications and adverse effects — The TCC is contraindicated in pregnant and breastfeeding women. Adverse effects include skin irritation, desquamation, and burning. Adverse effects of hydroquinone are discussed above. (See 'Adverse effects' above.)

Non-hydroquinone agents

Azelaic acid — Azelaic acid inhibits tyrosinase and shows antiproliferative and cytotoxic effects on several tumor cell lines in vitro [5,36]. In randomized trials, azelaic acid 20% cream has been shown to be as effective as 4% hydroquinone cream but more effective than 2% hydroquinone cream [44,45].

Skin lightening produced by azelaic acid typically takes one to two months to develop [39]. Between 1 and 5 percent of patients treated with 20% azelaic acid report pruritus, burning, stinging, and tingling. More rarely, patients experience erythema, dryness, rash, peeling, irritation, and dermatitis [2].

Of note, azelaic acid is one of the few skin-lightening agents that can be used for the treatment of melasma during pregnancy, if needed.

Kojic acid — Kojic acid is derived from a species of Aspergillus and Penicillium. It inhibits tyrosinase by chelating copper at the enzyme's active site. Kojic acid is widely used in Asia and is available in several OTC formulations at 2% in the United States, but when used as monotherapy, it seems to be less effective than hydroquinone [3,7,33]. Patients who are intolerant of hydroquinone may also consider kojic acid [8].

In a 12-week, split-face study, 40 Chinese women with melasma were treated on one-half of the face with kojic acid 2% in a gel containing glycolic acid 10% and hydroquinone 2% and on the other half with a comparable formula without kojic acid [46]. Melasma improvement of ≥50 percent (based on reduction in melasma area and degree of lightening) occurred in more sides treated with kojic acid than in the control sides (60 versus 47.5 percent, respectively).

Several studies have reported that kojic acid is a sensitizer, and it has been associated with mutagenicity and contact dermatitis [8,33].

Niacinamide — Niacinamide, also known as nicotinamide, is the physiologically active form of niacin or vitamin B3 [47]. Niacinamide blocks the transfer of melanosomes from melanocytes to keratinocytes. It has an anti-inflammatory effect and increases the biosynthesis of ceramides, as well as other stratum corneum lipids with enhanced epidermal permeability barrier function.

Several studies have documented the efficacy of niacinamide and niacinamide-based formulations for treatment of melasma. In an eight-week, left-right, randomized trial, 27 women with melasma were randomized to receive niacinamide 4% cream on one side of the face and hydroquinone 4% on the other [48]. The Melasma Area and Severity Index (MASI) score decreased by 70 percent from baseline in the sides treated with hydroquinone and by 62 percent in the sides treated with niacinamide. Moreover, good to excellent improvement was reported in 44 percent of patients with niacinamide and 55 percent with hydroquinone 4%. Niacinamide reduced the mast cell infiltrate and showed improvement in solar elastosis as well.

Rucinol — Rucinol is a resorcinol derivative that inhibits tyrosinase and tyrosinase-related protein-1 (TRP-1), another enzyme in the melanin biosynthetic pathway. The efficacy of rucinol was assessed in a randomized, split-face trial of 32 women with melasma who applied 0.3% rucinol serum or vehicle twice daily for 12 weeks, followed by open treatment of the full face for an additional 12 weeks [49]. At 12 weeks, the mean MASI score was lower for the rucinol-treated sides than for the sides treated with vehicle (6.2 versus 6.7, respectively).

Cysteamine — Cysteamine is a naturally occurring antioxidant produced during the coenzyme A metabolism cycle in all mammalian cells. The efficacy of cysteamine hydrochloride cream for the treatment of melasma has been documented in a few randomized trials [50-52]. In one trial that enrolled 50 patients treated with 5% cysteamine cream or placebo applied once daily for four months, the MASI scores and colorimetric values were lower in the cysteamine group than in the placebo group [51]. Side effects occurred in nearly all patients in the cysteamine group but were mild and included erythema, dryness, itching, burning, and irritation.

Undecylenoyl phenylalanine — Undecylenoyl phenylalanine is an antagonist of alpha-melanocyte-stimulating hormone, beta-adrenergic receptors, and stem cell receptors. In a randomized study, 40 women with melasma applied topical undecylenoyl phenylalanine 2% or vehicle twice daily for 12 weeks; 37 patients completed the study [53]. Seventeen of the 20 patients using undecylenoyl had a partial response, with 11 showing a moderate improvement and 6 showing a marked improvement. No patient showed a total response. Adverse effects were mild and included erythema, itching, and burning at the application site.

Tyrosinase inhibitors — Isobutylamido thiazolyl resorcinol is a potent inhibitor of human tyrosinase. In vitro studies have shown that isobutylamido thiazolyl resorcinol has a superior depigmenting activity compared with arbutin, kojic acid, and hydroquinone [54,55].

A randomized, split-face study assessed the efficacy of topical isobutylamido thiazolyl resorcinol 0.2% emulsion compared with hydroquinone 2% or no treatment in female patients with mild to moderate facial melasma [56]. All participants applied a daily sunscreen with a sun protection factor (SPF) of 30 or higher. At 12 weeks, isobutylamido thiazolyl resorcinol induced a greater decrease of the MASI score from baseline compared with hydroquinone. Moreover, MASI improvement was noted in more isobutylamido thiazolyl resorcinol-treated sides than in hydroquinone-treated sides (79 versus 61 percent, respectively).

In another trial, twice-daily isobutylamido thiazolyl resorcinol 0.2% was compared with hydroquinone 4% in 50 female patients [57]. At 90 days, the mean reduction of the MASI score compared with baseline was similar for isobutylamido thiazolyl resorcinol and hydroquinone (43 and 33 percent, respectively).

Topical methimazole — Methimazole is an oral agent commonly used to treat patients with hyperthyroidism. Studies have documented the lightening effects of a topical formulation of methimazole in female patients with melasma [58]. It has been shown to inhibit peroxidase and tyrosinase.

A randomized trial evaluated the efficacy and safety of methimazole 5% once a day versus 4% hydroquinone in 50 Iranian female patients with melasma [59]. At eight weeks, the reduction of the MASI score was greater in the hydroquinone group than in the methimazole group (76 versus 25 percent, respectively). Safety studies of topical methimazole have shown no impact on serum thyroid-stimulating hormone levels [60].

Topical malassezin — Malassezin is a natural indole compound of the skin microbiome produced by Malassezia furfur. It is an aryl hydrocarbon receptor agonist and potent antioxidant. A proof-of-concept, 22-week, double-blind study assessed its efficacy in 20 patients with melasma and photodamage [61]. Patients were treated for 14 weeks with an oil-in-water emulsion 0.1% to 1% and observed for an additional eight weeks. Malassezin induced a significant reduction in facial hyperpigmentation noted as early as four weeks. No relapse was noted among responders, with continued improvement through week 22.

Combination hydroquinone-free preparations — A combination hydroquinone-free preparation containing a variety of topical skin-lightening agents has been formulated to address the multiple pathways involved in the induction of hyperpigmentation [62,63]. These pathways include melanocyte activation, melanosome development, melanin synthesis, melanosome transfer, and keratinocyte differentiation and desquamation. It is available online and dispensed in clinicians' offices.

In a randomized trial of 43 patients with melasma or postinflammatory hyperpigmentation, a facial serum containing tranexamic acid, tetrapeptides, plankton extracts, niacinamide, phenylethyl resorcinol, and undecylenoyl phenylalanine showed overall comparable efficacy to hydroquinone 4% [62]. In another 12-week study assessing a different combination formulation, a facial serum containing 3% tranexamic acid, 1% kojic acid, and 5% niacinamide reduced the hyperpigmentation in 55 Brazilian women with mild to moderate melasma (n = 48) or postinflammatory hyperpigmentation compared with baseline.

Topical and intradermal tranexamic acid — Topical preparations of tranexamic acid have been evaluated for the treatment of melasma in a few studies [64-68]. A topical 5% solution of tranexamic acid was compared with 3% hydroquinone in a 12-week, randomized trial including 100 patients with melasma [64]. Both treatments reduced the MASI score by 27 percent from baseline. Mild erythema and irritation were reported in 19 of 50 patients in the hydroquinone group and only in 3 of 50 in the tranexamic group.

Intralesional microinjection of tranexamic acid may improve local tolerability of the drug, while resulting in a deeper and more even intradermal distribution of the drug [69]. In an open study, 85 patients received weekly microinjections for 12 weeks. MASI scores significantly decreased from 13 at baseline to 9 at 8 weeks and 7.6 at 12 weeks [69]. Eight (9 percent) of 85 patients rated the improvement as good (51 to 75 percent lightening) and 65 (76.5 percent) as fair (26 to 50 percent lightening). The remainder regarded the improvement as poor. All patients tolerated microinjections well [69].

ORAL AGENTS

Tranexamic acid — Oral tranexamic acid at the average dose of 250 mg twice daily is a promising adjunctive treatment for patients with melasma who do not respond to topical hydroquinone or triple combination cream alone [70]. (See 'Second-line therapies' above.)

Tranexamic acid, a hemostatic agent, is a synthetic derivative of lysine, which inhibits plasminogen from binding to its receptors expressed by keratinocytes [1,69]. This reduces ultraviolet (UV) light-induced plasmin activity and concentrations of free arachidonic acids and lowers prostaglandin production, tyrosinase activity in melanocytes, and the levels of melanocyte-stimulating hormone [3,69]. Tranexamic acid may also reduce levels of vascular endothelial growth factor (VEGF) and endothelin-1, chemical signals that promote angiogenesis, which appears to contribute to melasma pathogenesis [3,71,72]. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Antifibrinolytics and other pro-hemostatic therapies'.)

Several observational studies and randomized trials have documented the efficacy of oral tranexamic acid for the treatment of melasma [22-24].

●In a retrospective study of 561 melasma patients (91 percent female) from Singapore treated with tranexamic acid 250 mg twice daily for an average of four months, 90 percent of patients improved, 10 percent of patients experienced no improvement, and two patients showed worsening, according to the physician global assessment [25]. The response rate was higher in patients without family history of melasma compared with those with a family history (91 and 60 percent, respectively). Clinical improvement was apparent within two months of starting tranexamic acid, with a relapse rate of 27 percent. Moreover, 7 percent of patients developed adverse events, which were generally transient. One patient developed deep vein thrombosis and was later diagnosed with familial protein S deficiency, which increases the propensity to develop abnormal blood clots.

●In a single-center, randomized study, 44 Hispanic patients with moderate to severe melasma were treated with 250 mg tranexamic acid twice daily or placebo [22]. After three months, the modified Melasma Area and Severity Index (MASI) scores declined by 49 and 18 percent in the tranexamic acid and placebo groups, respectively. In patients with severe melasma, the reductions were 51 and 19 percent, respectively. Three months after treatment ended, the reductions were 26 and 19 percent with tranexamic acid and placebo, respectively. No serious adverse events were seen in either group.

●A 12-week, Indian, randomized trial that included 130 patients with facial melasma evaluated the efficacy of oral tranexamic acid 250 mg twice daily in combination with once-daily application of a triple combination cream (containing fluocinolone acetonide 0.01%, tretinoin 0.05%, and hydroquinone 2%) compared with the triple combination cream alone [73]. At 12 weeks, more patients in the combined treatment group than in the single treatment group showed a ≥75 percent improvement in the MASI score (66 versus 27 percent, respectively). At 24 weeks, recurrence occurred in 18 percent of patients in the tranexamic acid group compared with 64 percent in the triple combination cream group. Gastrointestinal adverse events, including gastritis, nausea, and vomiting, occurred in approximately 15 percent of patients in the tranexamic acid group.

Although oral tranexamic acid has an overall good safety profile, it should be considered a second-line therapy for melasma. Adverse effects include abdominal bloating, headache, tinnitus, menstrual irregularities, and, in rare cases, deep vein thrombosis. Therefore, patients should be thoroughly screened for thrombotic risk factors before starting oral tranexamic acid [3,25]. Relapses occur upon discontinuing oral therapy.

Polypodium leucotomos — Extracts of Polypodium leucotomos, a fern native to Central and South America, are attracting increasing attention as a possible oral treatment for melasma and other pigmentary diseases [1,74-76]. P. leucotomos promotes expression of the p53 suppressor gene, modulation of inflammatory cytokines, and upregulation of endogenous antioxidant systems, and it inhibits cyclooxygenase-2 (the inducible enzyme responsible for prostaglandin production) triggered by UV radiation [10].

Clinical studies of oral P. leucotomos have produced mixed results. A small, randomized trial including 33 Hispanic women with melasma compared 240 mg oral P. leucotomos extract with placebo three times daily for 12 weeks with the use of a sun protection factor (SPF) 55 sunscreen [75]. The melanin index (the difference between pigmented and adjacent normal skin measured using narrowband reflectance spectrophotometry) improved by approximately 29 and 14 percent in the P. leucotomos and placebo groups, respectively, between baseline and week 12. MASI scores also significantly improved in both groups. However, no statistically significant difference emerged between the groups on either outcome.

P. leucotomos extract may hasten clinical improvements when added to hydroquinone. A randomized study analyzed 33 Southeast Asian females receiving treatment for melasma with 4% topical hydroquinone and an SPF 50+ sunscreen plus oral P. leucotomos extract or placebo for 12 weeks [29]. At 12 weeks, 31 and 6 percent of the P. leucotomos and placebo groups, respectively, showed at least a 75 percent improvement in MASI scores. No major adverse effects of treatments were reported.

Indeed, based on a review of the literature, doses of P. leucotomos extract between 480 and 1200 mg daily do not seem to be associated with clinically significant adverse events [1].

Glutathione — Glutathione, a tripeptide consisting of glutamate, cysteine, and glycine, has multiple actions that combine to produce a skin-whitening effect. It inhibits tyrosinase, is an endogenous antioxidant, reduces inflammation, and can skew production from black or brown eumelanin to pheomelanin, which is yellow-red [3,77]. Because the ratio between the two forms of melanin determines skin color, an increase in pheomelanin lightens skin.

The effects of 500 mg glutathione lozenge taken orally once daily for eight weeks was evaluated in an open study in 30 Filipino women [77]. Patients were evaluated every two weeks. In sun-exposed skin, the melanin index significantly and steadily decreased compared with baseline at all assessment times. Buccal glutathione also decreased the melanin index compared with baseline in sun-protected skin. Ninety percent of patients stated that buccal glutathione produced a moderate skin-lightening effect, and the remainder reported a mild effect. There were no serious adverse effects, although two participants withdrew due to sore gums and the taste and consistency of the lozenge.

A topical glutathione 2% lotion was compared with vehicle alone in a randomized, split-face study including 30 Filipino women (mean age 36) [78]. Patients applied the lotion twice daily for 10 weeks. At week 10, 67 percent of the glutathione-treated sides exhibited skin whitening compared with 3 percent of the vehicle-treated sides. Moreover, glutathione showed a rapid onset of action, with 13 percent of treated sides exhibiting skin whitening at six weeks. No adverse events related to the application of topical glutathione were reported.

CHEMICAL PEELS — Chemical peeling involves the topical application of a wounding agent, wherein the desired outcome is a controlled regeneration of the skin, depending on the depth of penetration of the specific agent used (table 1 and figure 1).

Types of chemical peels — Chemical peel agents remove definite skin layers (eg, superficial, medium-depth, and deep), which triggers epidermal regeneration, and are thus classified according to the histologic depth of peeling into superficial very light, superficial light, medium-depth, and deep peels (table 1 and figure 1) [3,79]. The majority of clinicians using chemical peels for melasma utilize superficial or medium-depth peels. These include glycolic acid, other alpha-hydroxy acids, salicylic acid, Jessner's solution, and trichloroacetic acid. Trichloroacetic acid is considered the gold standard for peeling. Trichloroacetic acid precipitates epidermal proteins, causing sloughing and necrosis of the treated area. It can be used as a superficial or medium-depth peeling agent. The extent of wounding is concentration dependent. Although trichloroacetic acid is no longer sold as a pharmaceutical in the United States, it remains available through nonpharmaceutical channels and in use globally. (See "Chemical peels: Principles, peeling agents, and pretreatment assessment" and "Chemical peels: Procedures and complications".)

Efficacy

●Glycolic acid – Glycolic acid is the most extensively studied peeling agent for melasma [3,80].

•In a review of studies assessing the efficacy of chemical peels (including glycolic acid, lactic acid, Jessner's solution, tretinoin, and salicylic acid) for the treatment of melasma in patients with darkly pigmented skin, glycolic acid peeling was associated with a moderate response in approximately one-half of the patients, with patients having the epidermal form of melasma showing the best response [21].

•In a study of 40 Indian women with moderate to severe melasma, serial 30% and 40% glycolic acid peels plus daily use of hydroquinone 5% and tretinoin were compared with the daily use of hydroquinone 5% and tretinoin alone. Significantly greater improvement occurred in patients treated with 30% and 40% glycolic acid peels plus daily use of the topical lightening formulation compared with daily use of only the topical formulation.

•In an eight-week, randomized study evaluating a 35% glycolic acid full-face peel alone or in combination with a 10% or 20% trichloroacetic acid spot peel in 30 patients with facial melasma, the mean reduction in the Melasma Area and Severity Index (MASI) score from baseline was similar in all groups [81]. One-third of patients in the trichloroacetic acid groups experienced transient, postinflammatory hyperpigmentation.

•In a split-face study comparing the efficacy of a peeling solution that included azelaic acid 20%, resorcinol 10%, and phytic acid 6% versus a glycolic acid 50% in 42 women with skin type IV or less, both treatments resulted in a 50 percent reduction of the baseline MASI score. However, adverse effects, including protracted burning and dyspigmentation, occurred in 32 and 36 percent of the sides treated with glycolic acid peel, respectively, versus none of those treated with azelaic acid 20%, resorcinol 10%, and phytic acid 6% peel [82].

•The efficacy of a superficial peel containing glycolic acid and several other alpha-hydroxy acids combined with activated vitamin C was evaluated in a study including 21 women and 4 men aged 25 to 56 years with Fitzpatrick skin types IV or V. Patients received four chemical peels at one- to two-week intervals [79]. At eight weeks, improvement in pigmentation, pore size, and skin evenness was noted, with 96 percent of patients reporting at least fair improvement. No notable side effects or complications emerged.

●Salicylic acid – Salicylic acid is a lipophilic, superficial peeling agent. The efficacy of 20% to 30% salicylic acid peeling has been documented by one of the authors and others in the treatment of melasma [83,84]. However, in a split-face, randomized study including 20 Latin American women with moderate to severe, bilateral melasma treated on both sides with twice-daily 4% hydroquinone, the addition of 20% to 30% salicylic acid peels every two weeks for four times on one side was not more effective than hydroquinone alone in improving melasma [85].

●Trichloroacetic acid – In a study of 40 female patients with a minimum MASI score of 10, trichloroacetic acid 10% to 20% peels were similarly effective as glycolic acid 20% to 30% peels in reducing MASI scores [86]. Patients were peeled every two weeks. At 12 weeks, a good or very good response as assessed by patients was achieved by 75 percent of patients in the glycolic acid group and 65 percent of those in the trichloroacetic acid group, but the difference was not statistically significant.

Adverse effects — Possible adverse effects of chemical peels include infection, scarring (although this is rare during superficial peels), allergic reactions, milia, acneiform eruptions, persistent erythema (more than three weeks), and pigmentary changes [87]. Due to the risk of pigmentation and scarring, deep and medium-depth chemical peels should be used with caution in patients with darker skin tones [7,21,87].

LASERS AND LIGHT THERAPIES

Types of lasers/light sources — The principles dictating the use of lasers and light sources in melasma are based on the theory of selective photothermolysis. This concept proposes that the unique spectrum of light emitted by a specific laser is absorbed selectively by a cell or tissue type. Pulses of light that are brief and shorter than the thermal relaxation time of melanosomes are preferentially absorbed by pigmented structures in tissue and can cause selective heating and thermal damage to the pigmented structures [88-90]. Structures in the skin differ in the wavelengths that they absorb and the resulting thermal damage. This allows lasers to target specific chromophores, such as hair, tattoo ink, or excessive melanin, with little collateral damage to the surrounding skin [6]. Moreover, different wavelengths of light penetrate the skin to varying depths, allowing clinicians to target the particular depth of pigment in melasma (table 4). (See "Laser and light therapy for cutaneous hyperpigmentation".)

●Nonablative fractional lasers – Epidermal pigmentation is most likely to respond to a 1927 nm nonablative fractional laser. Dermal melasma may be more sensitive to lasers emitting wavelengths of 1440, 1540, and 1550 nm [6]. Nonablative fractional lasers seem to be associated with the longest delay in recurrence, followed by intense pulse light (IPL) and quality-switched (QS) lasers, the last having the most rapid recurrence rate [6].

●Quality-switched neodymium-doped yttrium aluminum garnet (QS Nd:YAG) – The QS Nd:YAG laser is the most commonly used laser for melasma [91], despite a relatively rapid relapse rate [6]. QS Nd:YAG lasers use a wavelength of 1064 nm, which is better absorbed by melanin than other skin structures. The QS Nd:YAG laser also damages the upper dermal vascular plexus, which is abnormal in melasma, and promotes collagen formation in the surrounding dermis [91].

●Pulsed dye laser (PDL) – Angiogenesis contributes to melasma pathogenesis [71,72,92]. The PDL is the gold standard for vascular lesions and, therefore, can target the vascular component of melasma [92,93].

●Intense pulsed light (IPL) – IPL delivers a broad spectrum of noncoherent light with a range of 500 to 1200 nm [91]. The clinician can modulate various parameters, such as wavelength and the number, duration, and delay of pulses, allowing for more accurate targeting of the chromophore. Absorption of light by melanin results in thermolysis. This forms melanin-containing "crusts" that migrate to the cornified layer of the epidermis, from where they are shed. One study reported excellent results (80 to 100 percent reduction in hyperpigmented areas and dark tones) with IPL in 47 percent of 38 patients, good results (60 to 79 percent) in 29 percent, and moderate results (40 to 59 percent) in 13 percent [94]. IPL targets all pigment in the skin and, therefore, may damage perilesional normal skin. IPL is thus not recommended in patients with darker skin tones (Fitzpatrick skin types IV through VI).

Efficacy — Over the years, many studies have evaluated the effect of different laser protocols for melasma with varying results. However, most studies are small, only a few are direct comparisons with other treatments, and, as laser treatment is difficult to blind, laser studies are less robust than randomized, controlled trials [2]. Moreover, the large heterogeneity of studies of laser treatment for melasma makes drawing robust conclusions about relative efficacy and tolerability difficult [6].

●In a split-face, randomized study, 22 Thai patients received five weekly treatments with a QS Nd:YAG laser combined with 2% hydroquinone or hydroquinone 2% alone [95]. On the laser-treated side, colorimetric relative lightness improved by 93 percent and the mean Melasma Area and Severity Index (MASI) score by 76 percent compared with 20 and 24 percent, respectively, on the control side. Three patients developed mottled hypopigmentation, four experienced rebound hyperpigmentation, and melasma recurred in all subjects.

●In a series of 40 patients from Korea who received 10 weekly treatments with a QS Nd:YAG laser, the mean modified MASI score decreased by 54 percent from baseline at 10 weeks. Thirty patients showed at least a fair improvement, and only four subjects showed no benefit. Two patients exhibited mottled hypopigmentation and rebound hyperpigmentation [96].

●The combination of microdermabrasion followed immediately by QS Nd:YAG was evaluated in 27 women with melasma that was refractory to other treatments. Patients used sunscreen and topical hydroquinone with either tretinoin or vitamin C. On average, patients received 2.6 treatments at four-week intervals. Most patients showed more than 50 percent clearance within a month of their first treatment. At 3 to 12 months after the end of treatment, 81 percent of the patients showed more than 75 percent clearance and 40 percent showed more than 95 percent clearance. Mild post-treatment erythema after the microdermabrasion, which lasted 30 to 60 minutes, was the only adverse event observed [97].

Adverse effects — Worsening of hyperpigmentation or mottled hypopigmentation may occur as a result of laser therapy. Patients should be instructed to adopt rigorous sun-protective measures after treatment, including sun avoidance and daily use of sunscreen. (See 'Photoprotection' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Melasma and hyperpigmentation disorders".)

SUMMARY AND RECOMMENDATIONS

●General considerations – The management of melasma is often challenging, with incomplete responses in many cases and frequent relapses. In most cases, a multimodality approach is required, incorporating photoprotection, skin lighteners, exfoliants, antioxidants, and resurfacing procedures, based on the patient's characteristics and clinical presentation. (See 'Approach to treatment' above.)

●Approach to treatment (algorithm 1)

•Photoprotection – For all patients with melasma, we suggest daily use of a broad-spectrum sunscreen with a sun protection factor (SPF) of 50 or higher (Grade 2C). Colored formulations (tinted sunscreens) containing iron oxide provide additional protection from visible light and can be used for cosmetic camouflage both during active and maintenance treatment. Sunscreen should be applied in adequate amounts in the morning and reapplied every two to three hours while outdoors. (See 'Photoprotection' above and 'Cosmetic camouflage' above.)

•Mild melasma – For patients with mild melasma, we suggest hydroquinone 4% cream as first-line therapy rather than non-hydroquinone agents (Grade 2C). Hydroquinone can be applied to the affected areas once or twice daily for two to four months and up to six months. Non-hydroquinone skin lighteners (eg, azelaic acid, kojic acid, niacinamide), alone or in combinations (table 2), can be used as alternative first-line therapies, particularly in patients who do not tolerate or have a demonstrated allergy to hydroquinone. (See 'First-line therapies' above and 'Hydroquinone' above and 'Non-hydroquinone agents' above.)

•Moderate to severe melasma – For patients with moderate to severe melasma, we suggest the fluocinolone, hydroquinone, and tretinoin triple combination cream (TCC) rather than hydroquinone 4% cream alone as initial treatment (Grade 2B). The cream is applied nightly for two to four months. (See 'First-line therapies' above and 'Triple combination cream' above.)

●Second-line therapies

•Chemical peels – Superficial chemical peels (glycolic acid, other alpha-hydroxy acids, salicylic acid, Jessner's peel, and trichloroacetic acid (table 1)) are a treatment option for patients with melasma that does not respond to topical skin lightening therapies alone. Several peeling sessions (approximately five to six) at two- to four-week intervals are generally required. Regular use of hydroquinone or non-hydroquinone lightening agents should be continued between the peeling sessions (table 2). (See 'Second-line therapies' above and 'Chemical peels' above.)

•Laser/light therapies – Lasers and light therapies are third-line therapies for melasma, appropriate for patients in whom topical treatments and often chemical peels have failed to produce adequate improvement (algorithm 1). They should be used with great care and caution, particularly in patients with darker skin to minimize the risk of postinflammatory hyperpigmentation. (See 'Third-line therapies' above and 'Lasers and light therapies' above.)